title: The Janus face of the heme oxygenase/biliverdin reductase system in Alzheimer disease: it's time for reconciliation.
abstract: Alzheimer disease (AD) is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. These clinical features are due in part to the increase of reactive oxygen and nitrogen species that mediate neurotoxic effects. The up-regulation of the heme oxygenase-1/biliverdin reductase-A (HO-1/BVR-A) system is one of the earlier events in the adaptive response to stress. HO-1/BVR-A reduces the intracellular levels of pro-oxidant heme and generates equimolar amounts of the free radical scavengers biliverdin-IX alpha (BV)/bilirubin-IX alpha (BR) as well as the pleiotropic gaseous neuromodulator carbon monoxide (CO) and ferrous iron. Two main and opposite hypotheses for a role of the HO-1/BVR-A system in AD propose that this system mediates neurotoxic and neuroprotective effects, respectively. This apparent controversy was mainly due to the fact that for over about 20years HO-1 was the only player on which all the analyses were focused, excluding the other important and essential component of the entire system, BVR. Following studies from the Butterfield laboratory that reported alterations in BVR activity along with decreased phosphorylation and increased oxidative/nitrosative post-translational modifications in the brain of subjects with AD and amnestic mild cognitive impairment (MCI) subjects, a debate was opened on the real pathophysiological and clinical significance of BVR-A. In this paper we provide a review of the main discoveries about the HO/BVR system in AD and MCI, and propose a mechanism that reconciles these two hypotheses noted above of neurotoxic and the neuroprotective aspects of this important stress responsive system.
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Barone
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Domenico
authors.affiliation: Institute of Pharmacology, Catholic University School of Medicine, Largo F. Vito, Rome, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Mancuso
authors.affiliation: Department of Chemistry, Center of Membrane Sciences, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA. Electronic address: dabcns@uky.edu.
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006801:Humans; D008959:Models, Neurological; D018384:Oxidative Stress; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism*
chemical_list: D006419:Heme Oxygenase (Decyclizing); D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase
keywords: 3-NT; 3-nitrotyrosine; 4-hydroxy-2-nonenal; ARE; Aging; Alzheimer disease; BVR-A; Biliverdin reductase; HNE; HO-1/2; Heme oxygenase; Mild cognitive impairment; Oxidative stress; PC; antioxidant responsive elements; biliverdin reductase isoform A; heme oxygenase isoform 1 or 2; protein carbonyls